Our objectives are to develop mathematical models and computer simulations to examine the interplay among microvasculature rheology, blood chemistry, oxygenation and red cell sickling, and to relate them to altered physiology of sickle-cell disease. Particular emphasis will be placed on the investigation of vascular crisis: key components of this crisis model will be derived from studies of rheological and oxygen transport phenomena in the microcirculatory system and the molecular biochemistry of the sickling process. In collaboration with clinical and experimental investigators, our previously developed physiological models for blood chemistry, microcirculation fluid mechanics, red blood cell kinetics, and renal function will be employed and extended to investigate: 1. Initiation, persistance, arrest, and treatment of vascular occlusive crisis, 2. The polymerization and blood chemistry of HbSS, 3. Hematological compensation, and changes in the erythropoietic system related to sickle-cell disease and its treatment. The models will be employed in experimental design, therapeutic trials, assessment of toxicity effects, treatment design and improvement, and to identify the reasons for the considerable variation which exists from patient to patient.